The incidence of prostate cancer (PCa) in the US and Western countries is much higher than that in Asia. High soy consumption has been proposed to reduce PCa risk. However, recent epidemiologic studies did not find evidence for health benefits of soy diet on PCa prevention in Western populations. To date, we still do not have a clear picture of the role that soy may play in PCa prevention. Given higher soy exposure levels found in Asian infants than American infants, and enhancement of PCa prevention with early soy exposure in animal studies, it is thought that timing of soy exposure may be a factor for the differing outcomes of soy's protection against PCa in Western versus Asian populations. Genistein (GEN), a major soy isoflavone, alters DNA methylation when given early in life. However, it remains unknown if the early soy exposure modulates gene methylation in the prostate gland, thereby reducing PCa risk later in life. The goal of the proposed research is to investigate the epigenetic basis of early dietary soy isoflavone intake, with a focus on identifying the gene methylation targets that may mediate the protective effects on PCa prevention. We hypothesize that GEN, especially when given early in life, serves as a methylome caretaker in the prostate by preventing or rectifying aberrant DNA methylation changes during the onset of precancereous lesion formation. Two specific aims are proposed: Aim 1: Determine the effects of timing of GEN supplementation on the efficacy of chemoprevention against Prostate Intraepithelial Neoplasia (PIN). Aim 2: Identify and characterize gene methylation targets for PIN prevention by early exposure to dietary GEN. In Aim 1, we will use a rat model to evaluate the chemopreventive efficacy of GEN on preventing sex hormone induction of PIN, which is believed to be PCa precursor. We predict that lifelong GEN exposure, started after conception, is more effective than GEN exposure limited in adulthood. In aim 2, we propose to use high throughput methylation arrays and integrated bioinformatics to identify signature gene methylation marks that may serve as molecular mediators or biomarkers for the enhancement of PCa prevention in response to early soy consumption. We will also use a knowledge-based approach to determine the effects of early soy exposure on potential methylation markers for prostate cancer risk assessment. We will determine if developmental reprogramming of the candidate genes occurs early in the life-time GEN regimen. Findings from this proposal should enhance our understanding of the relationships between diet, epigenetics and cancer prevention. This proposal may embark on a new research direction to investigate if timing of soy exposure and epigenetics as critical factors determining the outcome of dietary soy intervention on PCa.